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'Gold standard’ model for evaluating novel therapies offers hope for children with leukaemia

9 May 2017

Leukaemia causes more deaths in childhood than any other cancer. New treatments are needed, but also more reliable tests to decide which drugs should go to clinical trial. Collaborative research at Bristol has delivered a pioneering model of childhood leukaemia that is far more accurate than standard laboratory tests in evaluating novel therapies.

Current survival rates for children with leukaemia have reached a plateau. A fifth of children with acute lymphoblastic leukaemia (ALL) will relapse after treatment, and of these, most will not survive. Since current treatments for childhood leukaemia are very toxic and can be life-threatening, intensifying these therapies offers very little hope of increasing survival rates.

Most testing of new leukaemia drugs prior to clinical trials is conducted in vitro (on cell cultures in the lab). However, these don’t show the action of the drugs in vivo (ie on whole organisms), making the results potentially unreliable.

Researchers at Bristol’s School of Cellular and Molecular Medicine have developed a model for testing leukaemia drugs that promises to provide more reliable indications of clinical effectiveness. The model involves injecting patient material directly into immune-compromised mice. The team used this mouse model to demonstrate that the natural medicine parthenolide (PTL) can eliminate human leukaemias. Previous research may have overlooked the therapeutic potential of the drug because in vitro tests of PTL yielded disappointing results.

This was the first time that human leukaemias have been shown to be eradicated in mice and illustrated the importance of using animal models of human leukaemia for drug evaluation studies. The next step was to validate the mouse model by testing whether the results matched those from real patients.

Dr Allison Blair led the research, in collaboration with Dr John Moppett (Consultant Haematologist, University Hospitals Bristol NHS Foundation Trust) and Dr Christina Halsey (University of Glasgow). The project went ahead with 12 months’ funding from the EBI Translational Acceleration and Knowledge Transfer (TRACK) Award. TRACK supports health projects that have the potential to translate into clinical practice or show commercial promise.

The researchers inoculated immune-deficient mice with samples from children with leukaemia from different clinical risk groups and measured the rate at which the disease established. Then they treated the mice with conventional drugs or combinations of drugs used to treat the children and monitored their response. Another group of mice acted as a control and were given no treatment (placebo). Finally, the team compared the results with how each child responded to the treatment.

Overall the model gave a true representation of disease progression.  Results observed after drug therapy were very similar to the way the children who donated their samples responded during their treatment. The model was more accurate than standard laboratory tests, indicating it may be a good predictor of a patient’s response to therapy. 

Dr Blair and her team intend to use the model to test new drugs in development and identify new therapeutic strategies that are effective at killing leukaemia cells, while causing minimal toxicity to normal cells.  This could help improve survival rates and reduce the problem of children being over-treated with toxic drugs.

They have since used the results of their research to support a multidisciplinary application to Action Medical Research and been awarded an EBI Translational Proof of Concept Award to develop novel therapeutic delivery systems to treat childhood ALL. A member of the research team, Rhys Morgan won a Junior Fellowship from the Kay Kendall Leukaemia Fund. In addition, they have entered into an agreement with a company called Stem Cell Therapeutics to test some of their novel cancer drugs in this leukaemia model. 

Since the experiments were completed at the end of January 2016, three abstracts and two full papers [1, 2] have been published.

Further information

[1]  Cox CV, Diamanti P, Moppett JP, Blair A. Investigating CD99 Expression in Leukemia Propagating Cells in Childhood T Cell Acute Lymphoblastic Leukemia. PLoS One. 2016; 11(10):e0165210 
doi: 10.1371/journal.pone.0165210

[2]  Diamanti, P, Cox, CV, Moppett, JP and Blair, A. Dual targeting of Hsp90 in childhood acute lymphoblastic leukaemia. Br J Haematol. 2016 
doi:10.1111/bjh.14275

Learn more about Dr Blair’s research on the University of Bristol website.

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